tomivosertib (eFT508)

Our findings reveal that on a ketogenic diet, treatment with eFT508 (also known as tomivosertib; a P-eIF4E inhibitor) restrains pancreatic tumour growth. Thus, our findings unveil a new fatty acid-induced signalling pathway that activates selective translation, which underlies ketogenesis and provides a tailored diet intervention therapy for cancer.

P2, N=16, Terminated, Effector Therapeutics | Completed --> Terminated; Terminated early due to a lack of efficacy.

Most notably, numerous non-monogenic ASD-NDD- and epilepsy-associated genes identified in patients harboring putative loss-of-function mutations, including protein truncating, or damaging missense variants, were translationally suppressed in TSC2 -Null NPCs, and their translation were reversed upon RMC-6272 or eFT-508 treatment. Our study here establishes the importance of mTORC1-eIF4F and MNK-eIF4E-mediated mRNA translation in TSC, ASD and other neurodevelopmental disorders and lay the groundwork for evaluating drugs in clinical development that target these pathways as a treatment strategy for TSC as well as ASD/NDD.

P2, N=68, Active, not recruiting, Effector Therapeutics | Trial completion date: May 2024 --> Dec 2024 | Trial primary completion date: Mar 2024 --> Oct 2024

P2, N=68, Active, not recruiting, Effector Therapeutics | N=180 --> 68

P2; Recruiting --> Active, not recruiting

P1, N=15, Recruiting, Northwestern University | Active, not recruiting --> Recruiting

P1, N=15, Active, not recruiting, Northwestern University | Recruiting --> Active, not recruiting

Furthermore, we tested three pharmacological MNK inhibitors (eFT508, CGP57380, and cercosporamide) and found that they were effective against radioresistant NPC cells and synergized with irradiation. Our research highlights the activation of MNK-mediated survival mechanisms in NPC in response to radiotherapy and the potential of combining radiation with MNK inhibitors as a sensitizing strategy. Notably, eFT508 is currently being investigated in clinical trials for cancer treatment, and our findings may prompt the initiation of clinical trials using eFT508 in radioresistant NPC patients.

MDSC infiltration and tumor growth were dampened in prostate cancer treated with the MNK1/2 inhibitor eFT508 and/or the AKT inhibitor ipatasertib, either alone or in combination with a clinically available MDSC-targeting immunotherapy. This work provides a therapeutic strategy that combines translation inhibition with available immunotherapies to restore immune surveillance in prostate cancer.

P1, N=19, Completed, Translational Research in Oncology | Active, not recruiting --> Completed | N=45 --> 19

P2; N=120 --> 180

P1, N=45, Active, not recruiting, Translational Research in Oncology | Recruiting --> Active, not recruiting

In addition, tomivosertib significantly augments the inhibitory effects of 5-FU and paclitaxel but not everolimus, suggesting that tomivosertib preferentially sensitizes gastric cancer to chemotherapy...Tomivosertib is now in phase 2 clinical trials. Our study provides pre-clinical evidence to initialize clinical trials for gastric cancer using tomivosertib in combination with chemotherapy.

P2, N=120, Recruiting, Effector Therapeutics | Not yet recruiting --> Recruiting | Initiation date: Dec 2020 --> Apr 2021

P2, N=120, Not yet recruiting, Effector Therapeutics

A selective MNK1/2 inhibitor eFT508 inhibited the phosphorylation of eIF4E but did not reduce TSC2-null cell growth. In contrast, a PI3K/mTOR inhibitor omipalisib blocked the phosphorylation of Akt and both S6K/S6 and 4E-BP/eIF4E branches, and additively decreased the growth of TSC2-null cells with rapamycin. Omipalisib, or another inhibitor of both major mTORC1 growth pathways and pAkt, might provide therapeutic options for TSC2-deficient cancers including, but not limited to, LAM.

P1, N=45, Recruiting, Translational Research in Oncology | Not yet recruiting --> Recruiting

In prior clinical studies, T had an acceptable safety profile as a single agent and in combination with anti-PD-L1 agent avelumab...36 pts continued on anti PD-1 antibody (Pembrolizumab and Nivolumab, 18 each) and 3 on anti PD-L-1 antibody (Durvalumab 2, Atezolizumab 1)... The addition of T to existing checkpoint therapy was well tolerated and manifested clinical activity including objective responses in pts with progression on existing checkpoint inhibitor. A Progression Free Survival rate at 24 weeks of 41% was noted in NSCLC patients. Additional studies evaluating the addition of T to checkpoint inhibitor therapy after progression on anti PD-1 or PD-L-1 therapy are planned.

P1, N=45, Not yet recruiting, Translational Research in Oncology